Hydrochloric Acid → HCID 86687698, compound

HRID 1473628Notes

Reaction equation

HRID 1473628 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.Cl[C:16]1[C:17]([CH:44]([F:46])[F:45])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][N:37]=4)(=[O:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:21]=1.Cl>O1CCOCC1>[CH:9]1([C:16]2[C:17]([CH:44]([F:45])[F:46])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]5[CH:41]=[CH:40][N:39]=[CH:38][N:37]=5)(=[O:33])=[O:34])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH:21]=2)[CH2:11][CH2:10]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 86687699HCID 86687699, compound

Product 1

HCID 86687698HCID 86687698, compoundYield 37.1%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A solution of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.59 mg, 0.011 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) methyl-t-butylether (8.48 mg, 0.011 mmol), potassium phosphate (0.190 g, 0.895 mmol), cyclopropylboronic acid (0.038 g, 0.448 mmol), and 1-(5-chloro-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 457; 0.108 g, 0.224 mmol) in 1.5 mL dioxane/0.5 mL water was heated to 180° C. in the microwave for 45 minutes. LC/MS showed product, so the aqueous layer was removed. The reaction mixture was treated with HCl (4N in dioxane) (0.224 ml, 0.895 mmol) and was allowed to stir for 10 minutes. The reaction mixture was then concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(5-cyclopropyl-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.040 g, 0.083 mmol, 37.0% yield). 1H NMR (MeCN-d3) δ: 8.65 (d, J=5.7 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.86-7.95 (m, 2H), 7.63-7.69 (m, 1H), 7.15-7.45 (m, 2H), 7.12 (s, 1H), 6.96 (s, J=6.3, 1H), 3.67 (s, 3H), 2.03-2.14 (m, 1H), 0.88-1.00 (m, 2H), 0.59-0.70 (m, 2H); (M+H)+=483.0.

Workup

  1. customso the aqueous layer was removed
  2. concentrationThe reaction mixture was then concentrated
  3. customPurification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-63ac59ac4ff94ecd993e4c48e90aabab
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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